Cephalosporins are one of the mainstays of antibiotic therapy, and third-generation cephalosporins are first-line agents for the treatment of many types of serious infections, including those of nosocomial origin. Gaps in activity of currently available third-generation cephalosporins such as cefotaxime, cefoperazone, ceftriaxone, and ceftazidime, and increasing reports of gram-negative bacilli resistance to some of these agents, especially Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp., make it necessary to investigate new compounds. Ceftazidime is a commonly prescribed third-generation cephalosporin used for empiric treatment of serious infections such as pneumonia, urinary tract infection, and skin and skin-structure infection but is found to be less effective alone and to develop resistance easily. Cefepime, a fourth-generation cephalosporin with a wide range of activity against grain-positive and gram-negative bacteria, including multi-resistant strains of enterobacteriaceae, is the drug of choice but has limited use due to multiresistant P. aeruginosa or Acinetobacter supp. and/or methicillin-resistant S. aureus. Hence, a combination of fourth generation cephalosporin along with aminoglycoside is required which has less toxicity and maximum compatibility as in the present invention.
The nephrotoxic effects of aminoglycosides (particularly gentamicin and tobramycin) can be increased by the concurrent use of cephalosporins (particularly cefalotin [or cephalothin]). However some cephalosporins (cefuroxime, cefotaxime, ceftazidime and cefipime) appear not to interact adversely. (Plager J E., Cancer 1976; 37: 1937-43). In present invention amikacin is used in combination with cefepime which has lesser nephrotoxicity as compared to other combinations. (Barbhaiya R H et al. Antimicrob Agents in Chemother 1992; 36: 1382-6)
Febrile neutropenia is a common consequence of anticancer chemotherapy with a neutrophil count of less than 500 cells/cubic mm (Hughes et al, 1997, level 2). Cancer patients receiving myelosuppressive chemotherapy develop severe neutropenia and are at a high risk of developing life-threatening infections (Charnas, Luthi & Ruch, 1997, level 1; Cometta et al, 1996). Bacterial infections are a common cause of morbidity and mortality in neutropenic cancer patients (Freifeld & Pizzo, 1997, level 9), with a microbiologic cause for the febrile episode being demonstrated in approximately 40% cases (Charnas, Luthi & Ruch, 1997, level 1). These patients are at risk of Enterobacteriaceae, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis and viridans streptococci infections (Charnas, Luthi & Ruch, 1997, level 1; Patrick, 1997). Since febrile neutropenic patients fail to mount a full inflammatory response, and the current diagnostic tests are not sufficiently rapid, sensitive or specific for identifying or excluding the microbial cause of a febrile episode, they may have to treated empirically. The prompt institution of present invention as suitable antibiotic therapy for febrile neutropenic patients, without waiting 24 to 48 hours for the results of blood cultures, dramatically reduces infection-related morbidity and mortality in the cancer population undergoing chemotherapy.
Hospital-acquired pneumonia (HAP) remains the most severe nosocomial infection in intensive care units (ICUs). Some factors influencing mortality have been identified. Bacteraemia and Pseudomonas aeruginosa or Acinetobacter spp. as causative agents increase mortality. Beta-lactams alone were always considered inadequate when P. aeruginosa and/or methicillin-resistant S. aureus were implicated as pathogen(s) or copathogen(s).
Treatment instituted before knowing the aetiology and antimicrobial sensitivities is empirical. Therefore, present invention provides the desired empirical therapy for control of these bacterial infections in HAP patients.
Infectious complications are an important cause of morbidity and mortality, especially in patients with cancer with profound and prolonged neutropenia following intensive chemotherapy for haematological malignancies. Thus, prompt administration of empirical broad-spectrum antibiotics at the onset of fever in neutropenic patients with cancer has been the standard care since the 1971 report by Schimpff et al; (New England Journal of Medicine 284, 1061-5) documenting reduction in mortality rates. Combination therapy with an aminoglycoside plus an anti-pseudomonal β-lactam has commonly been recommended because this approach provides broad-spectrum coverage, bactericidal activity and potential synergic effects, and minimizes the development of resistance during treatment. Piperacillin-tazobactam and ceftazidime have been used in combination with aminoglycoside like gentamycin and tobramycin, having nephrotoxicity and lesser efficacy in certain cases. The present invention provides a cutting edge over conventional therapies. (Cometta, A., Zinner, S., De Bock, R., Calandra, T., Gaya, H., Klastersky, J. et al. (1995)Antimicrobial Agents and Chemotherapy 39, 445-52).
Beaucaire G et al. 1999 in Ann Fr Anesth Reanim; February; 18(2):186-95 had studied comparison of cefepime (2 g×2/day)+amikacin (7.5 mg.kg-1×2/day)(=cefe-ami) and ceftazidime (2 g×3/day)+amikacin (7.5 mg.kg-1×2/day)(=cefta-ami) in patients under mechanical ventilation suffering from a nosocomial pneumonia. The efficacy rates of cefe-ami and cefta-ami combinations were similar in ICU patients under mechanical ventilation with a nosocomial pneumonia. However the cefe-ami association was significantly more efficient in the population with a bacteriologically documented pneumonia. Chudanova TV et. Al 2003; Antibiot Khimioter.; 48(7):29-32 studied the results of the use of cefepime (Maxipime) combination with amikacin vs ceftriaxon combination with amikacin in the treatment of 80 patients with different forms of hemoblastosis are presented. They found that the average period of the treatment with cefepime and amikacin equaled to 13 days (8 to 16). The treatment with cefepime+amikacin was successful in 38 out of 40 patients (95%). The average period of the treatment with ceftriaxon and amikacin equaled to 14 days (7 to 18). The efficacy of the treatment with ceftriaxon+amikacin was 60% (24 patients out of 40).
Miguel A. Sanz et al for the Spanish PETHEMA Group 2002. J Antimicrob Chemother. July; 50(1):79-88. In this prospective multicentre trial, 969 patients with 984 febrile neutropenic episodes were randomized to receive iv amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) or piperacillin-tazobactam (4 g/500 mg every 6 h). Clinical response was determined at 72 h and at completion of therapy. Drug-related adverse events were reported in 10% of cefepime plus amikacin versus 11% of piperacillin-tazobactam plus amikacin patients. Mortality due to infection occurred in a total of 10 patients (two cefepime, eight piperacillin-tazobactam).
Similarly Barbhaiya R H, et al. in their paper “Lack of pharmacokinetic interaction between Cefepime and Amikacin in Humans” (Antimicrobial Agents and Chemotherapy, July 1992, pp 1382-6), and Sanz, Miguel A, et al in their paper “Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin . . . ”(antimicrobial agents and Chemotherapy, 2002, pp 79-88 have mentioned about use of cefepime and amikacin co-administration.
Co-administering as mentioned in the prior art has a number of disadvantages as stated here:                A) Drugs mentioned as the combinations are administered one after the other.        B) These drugs are not available in a premixed combination. Moreover, one of the drug component is available as liquid (ready to use) and other as dry powder for injection.        C) There is complexity involved in administration of the drug as more number of pricks are required and the time of administration is also long.        D) The chances of nephrotoxicity increases in the case of excess administration of aminoglycoside.        
Some other shortcomings of individual administration or co-administration of amikacin and cefepime as done in the prior art are:                a) Treatment time is prolonged to about 20 days in case of individual administration of these drugs and to about 13 days in case of co-administration.        b) Cost to the patient is higher due to increased hospitalization time.        c) The failure rate is higher due to inconsistency of dose. Like Beaucaire G et al. 1999 used cefepime (2 g×2/day)+amikacin (7.5 mg.kg-1×2/day) where as amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) was used by Miguel A. Sanz et al. 2002.        
The individual administration of the amikacin and cefepime components of drugs described in the prior art fails to solve the treatment problem satisfactorily because of following reasons:                a) The components are administered one after the other and individually in different doses.        b) The components are administered either in equal proportions or the ratio is undefined and not fixed.        c) The success rate of such a treatment is not as per the desired levels.        
Also, adequate dose is not available to the patient and the chances of development of resistance increases in the case of prior art.
It is therefore submitted that the prior art does not address typical problems to which solutions are provided by the present invention.
The individual doses of amikacin and cefepime of prior art for their defined treatment time, are costlier than the combination of present invention. A working on the cost comparison is provided for reference.
Accordingly, there is a need to provide a total solution by providing a pharmaceutical composition of antibiotic composition useful for intramuscular and/or intravenous administration for hospitalization patients with acute or serious bacterial infections, particularly against multiresistant P. aeruginosa, or Acinetobacter supp. and/or methicillin-resistant S. aureus. 